- 期刊
Plasminogen Activator Inhibitor-1: The Expression, Biological Functions, and Effects on Tumorigenesis and Tumor Cell Adhesion and Migration
並列摘要
Plasminogen activator inhibitor-1 (PAI-1) is a primary regulator of urokinase-type plasminogen activator (uPA). It inhibits uPA by forming a covalent complex, thus blocking uPA's interaction with substrates. The half-life of active PAI-1 is ＜ 1 h and it is easily transformed to a more stable inactive latent form. By binding with vitronectin, PAI-1 can be stabilized and remained its activity. PAI-1 expression is regulated by many intrinsic factors (e.g. cytokines, growth factors, hormones, and lipids) and extrinsic factors (e.g. physical injury and DNA-damaging agents). PAI-1 is an essential regulator in physiological thrombotic/fibrinolytic process in vessel. It is also in the extracellular matrix (ECM) where it controls local proteolysis via inhibiting uPA. PAI-1 can regulate cell adhesion via either inhibition of uPA or interference with the binding between cellular integrins or uPA receptor (uPAR) and vitronectin. In addition, PAI-1 can regulate cell migration by inducing clearance receptor-mediated cycled attachment-detachment-reattachment of integrins. PAI-1 may have a role in regulating tumor invasion, angiogenesis and metastasis. Elevated levels of both uPA and PAI-1 are associated with a poor prognosis in many cancers. However, most in vivo experiments revealed: (1) High level (pharmacological level) of PAI-1 prevented angiogenesis and tumorigenesis; (2) Low level (physiological level) of PAI-1 conversely facilitated tumor growth and angiogenesis, and (3) While in PAI-1-deficient host, tumor growth and angiogenesis could not progress. The conclusions of PAI-1 in cancer development are still controversial. Because PAI-1 may play a role in tumor cell migration and invasion through antiproteinase activity and interference with cell attachment to ECM, some strategies can be considered to apply PAI-1 derivatives to cancer therapy.